Fibrosis is characterized by excessive matrix deposition in a tissue or an organ during a reactive or reparative process. It is a major public health burden being implicated in nearly 45% of natural deaths in the western world. Fibrosis is observed in multiple disease including kidney disease, idiopathic pulmonary fibrosis (IPF), scleroderma, and cardiovascular disease.
For example, fibrosis has specifically been observed in hypertension, which is characterized by systolic and diastolic blood pressure greater than about 130 and 80 mmHg, respectively. Normally, the capacitance property of the aorta blunts blood pressure elevation during systole and maintains diastolic pressure and tissue perfusion during diastole. However, the present inventors recently showed that hypertension causes a striking deposition of collagen in the aortic adventitia. This deposition of collagen is associated with marked alteration in aortic compliance indicative of increased stiffness. In vivo, this increase in aortic stiffness leads to a loss of Windkessel or capacitance function of the aorta, increasing systolic pressure and pulse wave velocity, decreasing diastolic pressure, and promoting hypertension-related end-organ damage. In particular, the augmentation of systolic pressure caused by aortic stiffening may increase the incidence of stroke, renal failure, and myocardial infarction.
As such, hypertension is a major risk factor for cardiovascular mortality and morbidity, predisposing to myocardial infarction, stroke and heart failure. In western societies, hypertension affects approximately 30% of adults and by age 70, 70% of individuals are hypertensive. Not only is hypertension highly prevalent, treatment thereof generally requires multiple agents and is often unsuccessful.
That said, it has recently become apparent that microRNAs (miRNAs) contribute to pathophysiology of numerous diseases. MicroRNAs (miRNAs) are short non-coding RNAs, which are present in plants, animals and some viruses. MicroRNAs are synthesized as pri-miRNA that contain a hairpin loop. The enzyme dicer removes the hairpin loop leaving a double stranded miRNA duplex. One strand joins a group of proteins called the argonaute complex while the other strand called the “passenger strand” is usually discarded. The argonaute-attached miRNA (now called the RNA induced silencing complex or RISC) then binds its target mRNAs and either enhances mRNA degradation or blocks translation. miRNAs often bind to mRNAs that encode proteins in common pathways, and can thus serve as regulators of important physiological processes.
Currently, little is known about the role of miRNAs in hypertension. For example, although it has been suggested that miR-145 is prevalent in vascular smooth muscle cells and that it regulates blood pressure, preliminary data of the present inventors have failed to confirm this. Another miRNA potentially related to hypertension is miR-155, which targets the angiotensin II receptor type I (AT1R). Overexpression of this blunts angiotensin II signaling in primary lung fibroblasts. miR-155 is prevalent in atherosclerotic plaques and in pro-inflammatory macrophages and its absence reduces atherosclerotic lesion formation in ApoE−/−mice. Thus, there remain very few, if any, treatment strategies available that specifically target the pathogenesis of fibrosis and/or collagen deposition associated with hypertension.
Accordingly, there remains a need in the art for treatment of conditions associated with fibrosis and/or collagen deposition, such as, for example, treatment of aortic stiffening